Pharmacokinetic Study of Antiretroviral Drugs and Related Drugs During and After Pregnancy

Verified September 2017 by National Institute of Allergy and Infectious Diseases (NIAID)

Sponsor:

National Institute of Allergy and Infectious Diseases (NIAID)

ClinicalTrials.gov Identifier:

NCT00042289

First Posted: August 1, 2002

Last Update Posted: September 20, 2017

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.
Read our disclaimer for details.

Collaborator:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The purpose of this study is to evaluate the pharmacokinetics (PKs) of antiretroviral (ARV) and tuberculosis (TB) medications in pregnant women and their infants. (Pharmacokinetics are the various interactions between a drug and the body.) This study will also evaluate the PKs of certain ARVs in postpartum women before and after starting hormonal contraceptives. The PKs of these drugs will be evaluated by measuring the amount of medicine present in blood and/or vaginal secretions.

HIV-infected pregnant women will be assigned to this arm if receiving one or more of the following ARV drugs/drug combinations but not receiving TB treatment: atazanavir/cobicistat, darunavir/ritonavir, darunavir/cobicistat, etravirine, elvitegravir/cobicistat, dolutegravir, tenofovir alafenamide fumarate (TAF), TAF/cobicistat, TAF/ritonavir, efavirenz, or lopinavir/ritonavir.

Note: As of February 2016, the study will no longer enroll women receiving etravirine or increased dose lopinavir/ritonavir.

Drug: atazanavir/cobicistat

Women will receive atazanavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: darunavir/ritonavir

Women will receive darunavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: darunavir/cobicistat

Women will receive darunavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: etravirine

Women will receive etravirine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: elvitegravir/cobicistat

Women will receive elvitegravir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: dolutegravir

Women will receive dolutegravir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: tenofovir alafenamide fumarate (TAF)

Women will receive TAF as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: TAF/cobicistat

Women will receive TAF/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: TAF/ritonavir

Women will receive TAF/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: efavirenz

Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: lopinavir/ritonavir

Women will receive lopinavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Experimental: Women taking ARVs with TB treatment

HIV-infected pregnant women will be assigned to this arm if receiving efavirenz, lopinavir/ritonavir, or nevirapine and TB treatment with at least one of the following TB drugs at study entry: rifampicin, ethambutol, isoniazid, or pyrazinamide.

Note: As of February 2016, the study will no longer enroll women receiving nevirapine.

Drug: efavirenz

Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: lopinavir/ritonavir

Women will receive lopinavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: nevirapine

Women will receive nevirapine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: rifampicin

Women will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: ethambutol

Women will receive ethambutol as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: isoniazid

Women will receive isoniazid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: pyrazinamide

Women will receive pyrazinamide as prescribed by their clinicians. (Dosage will vary for each participant.)

Experimental: Women taking no ARVs with TB treatment

HIV-uninfected pregnant women will be assigned to this arm if receiving at least two of the following first-line TB drugs at study entry: ethambutol, isoniazid, pyrazinamide, or rifampicin.

Drug: ethambutol

Women will receive ethambutol as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: isoniazid

Women will receive isoniazid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: pyrazinamide

Women will receive pyrazinamide as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: rifampicin

Women will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)

HIV-infected and HIV-uninfected pregnant women with or without ARVs will be assigned to this arm if receiving at least two of the following second-line TB drugs at study entry: kanamycin, amikacin, capreomycin, moxifloxacin, levofloxacin, ofloxacin, ethionamide/prothionamide, terizidone/cycloserine, para-aminosalicylic acid (PAS), high dose isoniazid (INH), bedaquiline, clofazamine, delamanid, linezolid, or pretomanid.

Drug: kanamycin

Women will receive kanamycin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: amikacin

Women will receive amikacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: capreomycin

Women will receive capreomycin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: moxifloxacin

Women will receive moxifloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: levofloxacin

Women will receive levofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: ofloxacin

Women will receive ofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: ethionamide/prothionamide

Women will receive ethionamide/prothionamide as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: terizidone/cycloserine

Women will receive terizidone/cycloserine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: para-aminosalicylic acid (PAS)

Women will receive PAS as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: high dose isoniazid (INH)

Women will receive high dose INH as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: bedaquiline

Women will receive bedaquiline as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: clofazamine

Women will receive clofazamine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: delamanid

Women will receive delamanid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: linezolid

Women will receive linezolid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: pretomanid

Women will receive pretomanid as prescribed by their clinicians. (Dosage will vary for each participant.)

HIV-infected women 2-12 weeks postpartum will be assigned to this arm if receiving one of the following ARV drug combinations and starting postpartum contraceptives: atazanavir/ritonavir/tenofovir, darunavir/cobicistat, atazanavir/cobicistat, or efavirenz AND starting combined oral contraceptives formulated with ethinyl estradiol; or atazanavir/ritonavir/tenofovir, efavirenz, atazanavir/cobicistat, or darunavir/cobicistat AND starting etonogestrel implant.

Note: As of February 2016, the study will no longer enroll women receiving atazanavir/ritonavir/tenofovir or efavirenz AND starting etonogestrel implant.

Drug: atazanavir/cobicistat

Women will receive atazanavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: darunavir/cobicistat

Women will receive darunavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: efavirenz

Women will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: atazanavir/ritonavir/tenofovir

Women will receive atazanavir/ritonavir/tenofovir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: ethinyl estradiol oral contraceptive

Women will receive ethinyl estradiol oral contraceptive as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug: etonogestrel implant

Women will receive etonogestrel implant as prescribed by their clinicians. (Dosage will vary for each participant.)

Detailed Description:

Pregnant women experience unique physiological changes that may result in clinically significant alterations in drug PKs. Unfortunately, there have been few clinical trials to study the PKs of ARV, TB, and hormonal contraceptive drugs in pregnant women. The development of appropriate dosing regimens for the HIV-infected pregnant woman is critical to the health of both mother and fetus. Overdosing may lead to maternal adverse events and increased risk of fetal toxicity, while underdosing may lead to inadequate virologic control, increased risk of developing drug resistance mutations, and a higher rate of perinatal HIV transmission. This study will evaluate the PKs of ARVs used during pregnancy; evaluate TB drugs used during pregnancy, both in women who are HIV-positive and also taking ARVs and in women who are HIV-negative and not taking ARVs; and evaluate the PKs of hormonal contraceptive medications taken along with ARVs.

There will be five main groups of study arms: HIV-infected pregnant women taking ARVs without TB treatment, HIV-infected pregnant women taking ARVs with first-line TB treatment, HIV-uninfected pregnant women taking no ARVs with first-line TB treatment, HIV-infected and HIV-uninfected pregnant women with or without ARVs with second-line TB treatment for drug-resistant TB, and HIV-infected postpartum women taking ARVs and hormonal contraceptives. Participants will not receive medications through this study—they will continue on ARV, TB, and/or contraceptive medications prescribed by their health care providers.

Women who are 20 0/7 weeks to 37 6/7 weeks pregnant will be enrolled in this study and will remain in the study for up to 12 weeks after delivery. Postpartum women will be enrolled at 2 to 12 weeks after delivery and followed until 6 to 7 weeks after starting contraceptives. Infants will be followed for 16 to 24 weeks of life. At all study visits, participants will undergo a medical history, a physical exam, and blood collection. At some visits, women in some arms will undergo a vaginal swab. Blood collection from the mother and the detached umbilical cord will occur during delivery. Intensive PK sampling will be performed at study visits during the second and third trimester of pregnancy and/or postpartum, depending on the study arm. Additional study visits may occur depending on the ARV drug regimen prescribed.

Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

Child, Adult, Senior

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Maternal Inclusion Criteria:

Participant must belong to one of the following 5 groups:

HIV-infected pregnant women greater than or equal to 20 weeks gestation NOT on TB treatment receiving one or more of the ARV drugs/drug combinations specified in the protocol

HIV-infected pregnant women greater than or equal to 20 weeks gestation receiving one of the ARV drugs/drug combinations specified in the protocol and TB treatment with at least one of the TB drugs, specified in the protocol, at study entry

HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the first-line TB drugs, specified in the protocol, at study entry

HIV-infected and HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the second-line TB drugs, specified in the protocol, at study entry

HIV-infected women 2 to 12 weeks (14 to 84 days) post-delivery receiving one of the ARV drug combinations listed in the protocol AND starting postpartum contraceptives as listed in the protocol

The woman must be stable on the ARV drug/drug combination and/or TB drug combination for at least 2 weeks prior to PK sampling

If a woman is receiving a specific generic ARV formulation, the protocol team has approved this formulation

HIV-infected pregnant women must be planning to continue on current ARV regimen until postpartum PK sampling is completed. HIV-infected postpartum women on hormonal contraceptives must be planning to continue on ARV and contraceptive regimens until final PK sampling is completed.

For HIV-infected women: confirmed HIV infection, documented by positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol.

HIV-uninfected pregnant women must have documented negative HIV antibody test during current pregnancy. Note: adequate source documentation, including the date of specimen collection, date of testing, test performed, and test result, must be available.

Participants enrolling in the 3rd trimester must enroll by 37 6/7 weeks gestation

Participant can provide legal informed consent per local regulations

If a woman has completed this study and becomes pregnant again, she may re-enroll in the study only if she is enrolled in a different arm than that studied during her initial enrollment

Maternal Exclusion Criteria:

Women on medicines known to interfere with absorption, metabolism, or clearance of the drug being evaluated (see protocol for more information). Rifampicin is permitted for women being evaluated for TB and ARV drug interactions.

If pregnant, carrying multiple fetuses

Clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely to require a change in the medicine regimen during the period of study

Infant Enrollment Criteria:

All infants of mothers enrolled during pregnancy (meeting criteria specified above) are enrolled, in utero, immediately after maternal enrollment.

Infant Requirements for Washout Pharmacokinetic Sampling:

Born to HIV-infected mother enrolled during pregnancy in an ARV arm (does not include infants born to HIV-uninfected mothers receiving TB drugs)

Birth weight greater than 1000 grams

Is NOT receiving disallowed medications described in Section 7 of the protocol

Does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the site investigator

Born after singleton delivery (not after multiple birth)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00042289